Autoregulation of an antibody response via network-induced auto-anti-idiotype

Abstract

The antibody response of a single outbred rabbit was studied throughout three rounds of injections with Micrococcus lysodeikticus vaccine over a 31-mo period. The first-round response was characterized by a vigorous anti- micrococcus response and a strong anti-IgG rheumatoid factor response. The second-round response consisted of a triad of interacting molecules: anti- micrococcal antibodies, autoanti-idiotypic antibodies specific for distinct clonotypes of the first-round anti-micrococcal antibodies, and Fc-specific anti-IgG rheumatoid factor. The interacting triple complex was detected because of the formation of an immune complex that became insoluble upon dilution of the serum. Complex formation was inhibited in the presence of saccharide compounds known to be major immunodominant determinants of the micrococcal cell-wall carbohydrate polymer. The same saccharides did not affect the reaction of rheumatoid factor with IgG. Direct-binding radioimmunoassays ruled out mediation of the dilution-precipitation reaction by soluble micrococcal antigens. Specific absorption of rheumatoid factor inhibited the dilution-precipitation reaction. Auto-anti-idiotypic antibodies were specifically purified from second-round sera, directly confirming the presence of these antibodies. Suppressive effects of auto-anti-idiotypic antibodies on distinct antibody clonotypes were shown by gel isoelectric focusing of first-, second-, and third-round sera. Clonotypes expressed in the first round of immunizations were reduced in quantity or absent when auto-anti-idiotypic antibodies were detectable. Greatly enhanced levels or initial synthesis of new clonotypes of anti-micrococcal antibodies were detected during the period of auto-anti-idiotype synthesis. The third-round sera, devoid of detectable auto-anti-idiotype, contained clonotypes characteristic of both first- and second-round antisera. Thus, auto-anti- idiotypic-mediated suppression appeared to be reversible. The data are interpreted as lending strong support for concepts of autoregulation of immune processes in normal outbred animals via an idiotypic network.

Regulation of natural antiallotype antibody responses by idiotype network-induced auto-antiidiotypic antibodies.

“…Strayer et al (37,38) have shown in the T15 system that antiidiotype suppression is long-lasting in the neonate but that it only exerts transient suppression in adults. Other studies from this lab (19) have verified the reversibility of natural auto-antiidiotype regulation in rabbits and the data from the experiment described in Fig. 5 suggest that the natural auto-antiidiotypic regulation that followed the natural antiallotype response was reversible.…”

“…It is tempting to speculate that the cross-reactive idiotopes found in this paper and in (19) and (35) that seem to be involved in idiotype regulation in normal outbred animals may be similar to, or identical with, the special class of regulatory idiotopes postulated by Paul and Bona (39). These idiotopes in (35) were found only in sera of rabbits which mounted auto-antiidiotypic responses.…”

“…Assays to detect antiallotype antibodies and anti-(antiallotype) antibodies were done as described earlier (19). Briefly, antiserum and 12si F(ab')2 fragments were mixed and complexes were precipitated with either monospecific goat anti-Fc or with 18% PEGE 6000 dissolved in borate-saline buffer, pH 8.0.…”

Regulation of monoclonal immunoglobulin G synthesis by antiidiotypic antibody in a patient with hypogammaglobulinemia.

“…It has also been shown in inbred as well as outbred animals that autoantiidiotypic antibodies arise during the course ofthe normal immune response and regulate idiotype expression (26)(27)(28). Thus, it is not unlikely that antiidiotypic antibody can inhibit antibody synthesis by normal B cells, and experiments in our laboratory indicate that antiidiotypic antisera to human antitetanus toxoid antibodies precisely do so (7).…”

Network Theory in Autoimmunity

“…The discovery of positive and negative interactions between T and B lymphocytes (7) and the possible involvement of idiotypes in clonal interactions (4) indicate that the immune system can recognize selfand is regulated by a complex idiotypic network (1)(2)(3)(4)(5). Idiotypes and autoantiidiotypes coexist in the repertoire of a single individual; autoantiidiotypes can be induced or occur spontaneously during the immune response (4,(25)(26)(27). These antiidiotypic antibodies can exert either positive or negative influences on antibody biosynthesis or on effector cell function (10,27 In this report we have examined the modulation of autoantibody activity by means of antiidiotypic antibodies.…”